11Beta-long-chain-substituted 19-nor-17alpha-pregna-1,3,5(10)-trien-17beta-ols with a 21,16alpha-lactone ring

ABSTRACT

This invention relates to new 19-nor-17α-pregna-1,3,5(10)-trien-17β-ols with a 21,16α-lactone ring with a long-chain substituent in 11β-position of general formula II  
                 
 
     in which R 11  means a straight-chain alkyl radical with 6 to 17 carbon atoms, and R 3  and R 13  have the meanings that are explained in more detail in the description. The compounds act in a tissue-selective manner as pure antiestrogens and are suitable for the production of pharmaceutical agents because of these properties.

[0001] This application claims the benefit of the filing date of U.S.Provisional Application Serial No. 60/374,516, filed Apr. 23, 2002.

[0002] This invention relates to new 11β-long-chain-substituted19-nor-17α-pregna-1,3,5(10)-trien-17β-ols with a 21,16α-lactone ring,process for their production and pharmaceutical preparations thatcontain these compounds as well as the use of these compounds for theproduction of pharmaceutical agents.

[0003] Estrogens exert their physiological action on receptor proteins,the estrogen receptors (ERs). In this case, these are nuclear-positiontranscription factors that can be activated by ligands. Until a fewyears ago, it was assumed that estrogens exert their action via a singlereceptor.

[0004] Only since 1996 has it become known that two subtypes of theestrogen receptor exist (ERα and ERβ) (Kuiper et al., Proc. Natl. Acad.Sci. USA 93, 1996, 5925-5930). Both are distinguished in theirexpression pattern in different tissues. Thus, for example, ERβpredominates over ERα in the rat prostates, while ERα predominates inthe rat uterus. Areas were identified in the brain in which in each caseonly one of the two ER subtypes is expressed (Shugrue et al., Steroids61, 1996, 678-681; Li et al., Neuroendocrinology 66, 1997, 63-67). BothERα and ERβ are expressed in bones (Kuiper et al., Frontiers inNeuroendocrinology 1998, 19: 253-286), blood vessels (Iafrati et al.,Nature Med. 1997, 3: 545-48) and normal breast tissue (Gustafsson andWarner, J. Steroid Biochem. Mol. Biol. 74, 2000, 245-248).

[0005] In malignant, degenerated breast tissue, an up-regulation of ERαexpression as well as a reduced ERβ expression were observed in severalindependent works (Leygue et al., Cancer Res. 58, 1998, 3197-3201; Iwaoet al., Int. J. Cancer 88, 2000, 733-736; Lacennec et al., Endocrinology142, 2001, 4120-4130; Roger et al., Cancer Res. 61, 2001, 2537-2541).ERβ knock-out mice (deficient ERβ) exhibit an abnormal epithelial growthof the breast and an over-expression of proliferation marker Ki67(Gustafsson and Warner, 2000). Also, an inverse correlation between ERβexpression and Ki67 was detected in humans (Roger et al., 2001). Inaddition, ERβ acts as an inhibitor of ERα transcriptional activity andlowers the cellular sensitivity to estradiol (Hall and McDonnell,Endocrinology 140, 1999, 5566-5578). These data support the hypothesisthat ERβ, i.a., shows a protective factor against the mitogenic activityof estrogens that is mediated by ERα. ERβ can therefore be regarded asan endogenic antagonist of ERα.

[0006] In patents by Katzenellenbogen et al. (WO 00/19994) and Loozen etal. (WO 00/31112), subtype-specific estrogen receptor ligands, i.a.,ERα-selective compounds, are described.

[0007] WO 01/00652 discloses 11β-long-chain-substituted estratrienes ofgeneral formula I,

[0008] in which R11 is a long-chain radical that has a nitrogen atom aswell as optionally a sulfur atom, which in addition can befunctionalized in terminal position with a perfluoroalkyl group or anoptionally substituted aryl radical. The compounds have at theirdisposal antiestrogenic or tissue-selective estrogenic properties andare suitable for the production of pharmaceutical agents.

[0009] In the un-prepublished application DE 100 48 634,19-nor-17α-pregna-1,3,5(10)-trien-17β-ols with a 21,16α-lactone ring aredescribed as selective estrogens, which show preference for estrogenreceptor α in contrast to standard estrogens such as estradiol.

[0010] The object of this invention consists in making available newcompounds that have in vitro a dissociation with respect to theirbinding to estrogen receptor preparations of rat prostates and rat uteriand in vivo an antiproliferative action via the preferentialantagonizing of ERα, without preventing the positive properties of theERβ. This also includes a preferential suppression of the expression ofERα without reduction of the ERβ expression.

[0011] The object is [achieved] according to this invention by thepreparation of novel 19-nor-17α-pregna-1,3,5(10)-trien-17β-ols with a21,16α-lactone ring with a long-chain substituent in 11β-position ofgeneral formula II

[0012] in which

[0013] R³ represents a hydrogen atom, a C₁₋₄-alkyl, C₂₋₆-acyl ortri(C₁₋₄-alkyl)silyl group or a group R¹⁸SO₂—,

[0014] whereby

[0015] R¹⁸ represents a group R¹⁹R²⁰N—,

[0016] in which

[0017] R¹⁹ and R²⁰, independently of one another, are a hydrogen atom, aC₁₋₅-alkyl radical, a group C(O)R²¹ and

[0018] in which

[0019] R²¹ represents a straight-chain or branched hydrocarbon radicalwith up to 6 carbon atoms, a C₃₋₇-cycloalkyl radical, an aryl radical,which optionally can be substituted, an aralkyl radical or an alkylarylradical,

[0020] and

[0021] R¹¹ means a straight-chain alkyl radical with 6 to 17 carbonatoms, and

[0022] R¹³ means a methyl or ethyl group.

[0023] Another subject of this invention relates to pharmaceuticalagents that contain a compound of general formula II or theirpharmaceutically acceptable addition salts with organic or inorganicacids.

[0024] Unless defined in more detail otherwise in terms of thisinvention, this is an aryl radical that optionally can be substituted bya phenyl, 1- or 2-naphthyl radical, whereby the phenyl radical ispreferred. Unless expressly indicated otherwise, aryl always alsoincludes a heteroaryl radical. Examples of a heteroaryl radical are the2-, 3- or 4-pyridinyl radical, the 2- or 3-furyl radical, the 2- or3-thienyl radical, the 2- or 3-pyrrolyl radical, the 2-, 4- or5-imidazolyl radical, the pyrazinyl radical, the 2-, 4- or 5-pyrimidinylradical or the 3- or 4-pyridazinyl radical.

[0025] As substituents for an aryl or heteroaryl radical, for example, amethyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio,methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine,iodine), hydroxy, amino, mono (C₁₋₈-alkyl) or di(C₁₋₈-alkyl)amino,whereby both alkyl groups are identical or different, anddi(aralkylamino), whereby both aralkyl groups are identical ordifferent, can be mentioned.

[0026] For substituent R¹¹, for example, hexyl, heptyl, decyl, anddodecyl can be mentioned as representatives of straight-chain alkylchains with 6 to 17 carbon atoms.

[0027] As representatives of alkyl radicals or straight-chain orbranched-chain alkyl groups with up to 12 carbon atoms in terms of R³,R¹⁹ and R²⁰ or R²¹, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,heptyl, and decyl can be mentioned. Methyl, ethyl, propyl and isopropylare preferred.

[0028] C₂₋₆-acyl radicals mean, for example, acetyl, propionyl, butyryl,valeroyl, isovaleroyl, pivaloyl, and hexanoyl.

[0029] Representatives of the above-mentioned C₃₋₇-cycloalkyl group canbe, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0030] The hydroxyl group at C-atom 3 can be esterified with analiphatic, straight-chain or branched-chain, saturated or unsaturatedC₂₋₆-carboxylic acid. As such carboxylic acids for esterification, thefollowing are considered, for example: acetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, isovaleric acid or pivalicacid.

[0031] As examples of a tri(C₁₋₄-alkyl) group, a trimethylsilyl groupand a tert-butyldimethyl group can be mentioned.

[0032] According to the invention, compounds of general formula II

[0033] are preferred, in which

[0034] R³ means a hydrogen atom or a methyl group and R¹³ means a methylgroup, and R¹¹ can be selected from the group of the following sidechains: hexyl, octyl, decyl and dodecyl.

[0035] Especially preferred 11β-long-chain-substituted19-nor-17α-pregna-1,3,5(10)-trienes with a 21,16α-lactone ring are, forexample:

[0036]3,17β-Dihydroxy-11β-hexyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0037]3,17β-dihydroxy-11βoctyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0038]3,17β-dihydroxy-11β-decyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0039]3,17β-dihydroxy-11β-dodecyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0040] For the formation of pharmaceutically compatible salts of thecompounds of general formula II according to the invention, i.a.,hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acidare suitable as inorganic acids, and, i.a., acetic acid, propionic acid,maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid,oxalic acid, salicylic acid, tartaric acid, citric acid, lactic acid,malic acid, mandelic acid, cinnamic acid and methanesulfonic acid aresuitable as organic acids.

[0041] The substances of general formula II according to the inventionrepresent compounds that are distinguished by a new structural element,a 21,16α-lactone ring, compared to the compounds with long-chain11β-side chains that are known from the prior art. It was found that11β-substituted 19-nor-17α-pregna-1,3,5(10)-trien-17β-ols with a21,16α-lactone ring according to the invention selectively show, in asurprising way, an antagonistic action on the ERα. With the substancesaccording to the invention, it is possible preferably to antagonize theERα without preventing the positive properties of the ERβ. This alsoincludes a preferential suppression of the expression of ERα withoutreduction of the ERβ expression.

[0042] Biological Characterization of the Compounds According to theInvention

[0043] The substances of general formula II according to the inventionwere tested in various models. Via the selective inhibition of the ERα,the substances according to the invention exert an antiproliferativeaction in other hormone-modulated tumors in addition to the breasttissue.

[0044] Estrogen Receptor Binding Studies

[0045] Methodology

[0046] The binding affinity of the new selective antiestrogens wastested in competitive experiments with use of 3H-estradiol as a ligandon estrogen receptor preparations of rat prostates and rat uteri. Thepreparation of the prostate cytosol and the estrogen receptor test withprostate cytosol was performed as described in the literature (Testas etal., Endocrinology 109, 1981, 1287-1289).

[0047] The preparation of rat uterus cytosol as well as the receptortest with the estrogen-receptor-containing cytosol was performed inprinciple according to Stack and Gorski (Stack, Gorski, Endocrinology117, 1985, 2024-2032) with several modifications (Fuhrmann et al.,Contraception 51, 1995, 45-52).

[0048] The substances according to the invention, such as, for example3,17β-dihydroxy-11β-hexyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone(compound 1), have a higher binding affinity to the estrogen receptorfrom the rat uterus than to the estrogen receptor from the rat prostate(see Table 1). TABLE 1 Rat Uterus Rat Prostate Uterus-ER/ CompoundStructure ER (RBA) ER (RBA) Prostate-ER Estradiol

100 100 1 Compound 1

26.2 1.2 22

[0049] Compound 1:3,17β-Dihydroxy-11β-hexyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0050] RBA: Relative binding affinity

[0051] ER: Estrogen receptor

[0052] In this case, it is assumed that ERβ predominates in the ratprostate over ERα, and ERα predominates in the rat uterus over ERβ.Table 2 shows that the ratio of binding to prostate and uterus receptorscorresponds qualitatively to the quotient of the relative bindingaffinity (RBA) to human ERβ and rat ERα (Kuiper et al., Endocrinology138, 1996, 863-870). TABLE 2 hER α hER β ERβ/ Rat uterus Rat prost.Uterus-ER/ Estrogen Struktur RBA* RBA* ERα ER(RBA) ER(RBA) Prostata-EREstrodiol

100 100 1 100 100 1 Estron

60 37 0.6 3 2 0.8 17α- Estrodiol

58 11 0.2 2.4 1.3 0.5 Estriol

14 21 1.5 4 20 5 5-Andros- ten- diol

6 17 3 0.1 5 50 Genistein

5 36 7 0.1 10 100 Coumestrol

94 185 2 1.3 24 18

[0053] [Key to Table2:]

[0054] Struktur=Structure

[0055] Prostata=Prostate

[0056] Estron=Estrone

[0057] Androstendiol=Androstenediol

[0058] Genistein=Genisteine

[0059] *cited from: Kuiper et al. (1996), Endocrinology 138: 863-870

[0060] hER: human estrogen receptor

[0061] Cell Proliferation Assay

[0062] Breast cancer cell line MCF-7 is a hormone-dependent human cellline. The growth of these ER-positive cells is stimulated by estradioland can be antagonized with partial-agonistic and pure antiestrogens(Lippmann et al. 1976, Wakelin et al. 1991). The substances according tothe invention, for example3,17β-dihydroxy-11β-hexyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone(compound 1), exert an antiproliferative action on theestradiol-modulated tumors via the selective inhibition of the ERα.

[0063] Material and Methods

[0064] The readily characterized breast cancer cell line MCF-7 wasestablished from the pleural exudate of a 69-year-old patient withdisseminated breast cancer (Soule et al. 1973).

[0065] The cells are cultivated in RPMI medium 1640 without phenol red,1% L-glutamine, 200 mmol of insulin/ml and 10% FCS or CCS in anincubator at 37° C. and water vapor-saturated atmosphere with 5% CO₂.

[0066] The medium is changed every three to four days. Cells that growconfluently in the cell culture flask to 80-90% are passaged.

[0067] In the tests, the test substances were checked for theirestradiol-stimulated proliferation-inhibiting properties.

[0068] For the tests, the dissemination of a defined cell number in a96-hole plate is carried out in 200 μl medium/hole (5000 cells/hole).Two columns are filled only with medium as blanks. 24 hours later, afteradhesion of the cells has been completed, the medium is varied by addingthe substances to be tested. The test substances, dissolved as stocksolution in absolute ethanol (EtOH), are added at increasingconcentrations. In addition to a solvent control, an estradiol controlis also used. The test period is 7 days, within which the medium ischanged after three days. The proliferation is determined with thecrystal violet assay. This method is based on the staining of DNA in thenucleus by crystal violet (N-hexamethylpararosaniline) (Wakelin et al.1981). The intensity of the blue staining, which depends on the amountof crystal violet that is bonded to the DNA, can be quantified byspectral-photometric measurements. The extinction values correspond tothe amount of DNA and thus the number of cell nuclei. They are equatedas indirect parameters of the cell number (Gillies et al. 1986).

[0069] The cells are fixed at the end of the test with 25 μl ofglutardialdehyde solution (11%) per hole for 20 minutes at roomtemperature by a slight shaking. The perforated disk is rapped to removeexcess material, washed under running, demineralized water (VE-water)and air-dried. After 100 μl of crystal violet (0.1%, pH 4.5) is addedper hole to the fixed cells, it is shaken for 20 minutes at roomtemperature. After being washed and air-dried again, 100 μl of aceticacid (10%) is added per hole, shaken briefly, and the extinction at 595nm is measured in a spectral photometer (Kueng et al. 1989).

[0070] Results

[0071] As can be seen from diagram1,3,17β-dihydroxy-11β-hexyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone(compound 1) inhibits the growth of MCF-7 breast cancer cells. Adose-action relationship exists. At a concentration of 1×10⁻⁵ M, theestradiol-stimulated proliferation of the MCF-7 breast cancer cells isinhibited to 100%.

[0072] [Key to Diagram 1:]

[0073] Zellproliferation (% der Kontrolle mit E2)=Cell proliferation (%of the control with E2)

[0074] Kontrolle [ohne E2]=Control [without E2]

[0075] Kontrolle [mit 10-10 ME2]=Control [with 10-10 ME2]

[0076] Verbindung 1=Compound 1

[0077] Konzentration (M)=Concentration (M)

[0078] Pharmaceutical Preparations and Indications

[0079] The compounds of general formula II represent compounds withantiestrogenic action after peroral or parenteral administration.

[0080] Moreover, the compounds according to the invention are pureantiestrogens.

[0081] This invention comprises the novel substances as pharmaceuticalactive ingredients, their production, their therapeutic application andthe pharmaceutical dispensing forms that contain the new substances. Thechemical compounds are new steroidal ERα-selective antagonists.

[0082] The new selective ERα antagonists that are described in thispatent can be used as individual components or in combination inparticular with estrogens or antigestagens in pharmaceuticalpreparations. The novel selective ERα antagonists are suitable both fortreating estrogen-dependent diseases, such as, for example,endometriosis; breast cancers, endometrial carcinomas, and antiovulatoryinfertility, and for treating prostate cancers, prostate hyperplasias,and melanomas as well as lung cancers.

[0083] The compounds of general formula II can be used as components inthe products that are described in EP 346014 B1 that contain an estrogenand a pure antiestrogen, namely for simultaneous, sequential or separateuse for the selective estrogen therapy of perimenopausal orpostmenopausal women.

[0084] The compounds of general formula II can be used together withantigestagens (competitive progesterone antagonists) for treatinghormone-dependent tumors (EP 310 542 A).

[0085] Other indications in which the compounds of general formula IIcan be used are male hair loss, a diffuse alopecia, an alopecia that iscaused by chemotherapy as well as hirsutism (H.-S. Oh, R. C. Smart,Proc. Natl. Acad. Sci. USA, 93, 1996, 12525-12530).

[0086] The compounds of general formula II can also be used for theproduction of pharmaceutical compositions for male and female birthcontrol.

[0087] The compounds of general formula II according to the inventionand their acid addition salts are suitable for the production ofpharmaceutical compositions and preparations. The pharmaceuticalcompositions or pharmaceutical agents contain as active ingredient atleast one or more of the compounds of general formula II according tothe invention or their acid addition salts, optionally in combinationwith other pharmacologically active substances or pharmaceuticaladjuvants. The production of the pharmaceutical agents is carried out ina known way, whereby the known and commonly used pharmaceuticaladjuvants as well as other commonly used vehicles and diluents can beused.

[0088] As such vehicles and adjuvants, for example, those are suitablethat are recommended or indicated in the following bibliographicreferences as adjuvants for pharmaceutics, cosmetics and related fields:Ullmann's Enzyklopädie der technischen Chemie [Ullmann's Encyclopedia ofTechnical Chemistry], 4, 1953, 1-39; J. Pharm. Sciences, 52, 1963, 918ff; issued by Czetsch-Lindenwald, Hilfsstoffe für Pharmazie undangrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields];Pharm. Ind. 2, 1961, 72 ff; Dr. H. P. Fiedler, Lexikon der Hilfsstoffefür Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvantsfor Pharmaceutics, Cosmetics and Related Fields], Cantor KG, Aulendorfin Württemberg 1971.

[0089] The compounds of general formula II according to the inventioncan be administered orally or parenterally, e.g., intraperitoneally,intramuscularly, subcutaneously and percutaneously. The compounds canalso be implanted in the tissue.

[0090] Dosage

[0091] The amount of the compounds to be administered fluctuates withina wide range and can cover any effective amount. Based on the conditionto be treated and the type of administration, the amount of theadministered compound can be 0.1-25 mg/kg of body weight, preferably0.5-5 mg/kg of body weight. In humans, this corresponds to a daily doseof 5 to 1250 mg. The preferred daily dosage in humans is 50 to 200 mg.

[0092] For oral administrations, tablets, film tablets, coated tablets,capsules, pills, powder, solutions or suspensions or else depot formsare suitable. Suitable tablets can be obtained, for example, by mixingactive ingredient with known adjuvants, for example inert diluents suchas dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone,explosives such as corn starch or alginic acid, binders such as starchor gelatin, lubricants such as magnesium stearate or talc and/or agentsfor achieving a depot effect such as carboxyl polymethylene,carboxylmethyl cellulose, cellulose acetate phthalate or polyvinylacetate. The tablets can also consist of several layers.

[0093] Correspondingly, coated tablets can be produced by coating coresthat are produced analogously to the tablets with agents that arecommonly used in tablet coatings, for example polyvinyl pyrrolidone orshellac, gum arabic, talc, titanium oxide or sugar. In this case, thecoated tablet shell can also consist of several layers, whereby theadjuvants that are mentioned above in the tablets can be used.

[0094] Solutions or suspensions with the compounds of general formula IIaccording to the invention can in addition contain taste-improvingagents such as saccharine, cyclamate or sugar as well as, e.g.,flavoring substances such as vanilla or orange extract. In addition,they can contain suspension adjuvants such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

[0095] The compounds of general formula II that contain capsules can beproduced, for example, by the compound of general formula II being mixedwith an inert vehicle such as lactose or sorbitol and encapsulated ingelatin capsules.

[0096] To achieve a better bioavailability of the active ingredient, thecompounds of general formula II can also be formulated as cyclodextrinclathrates. To this end, the compounds are reacted with α-, β- orγ-cyclodextrin or derivatives of the latter (PCT/EP 95/02656).

[0097] For parenteral administration, the active ingredients can bedissolved or suspended in a physiologically compatible diluent. Asdiluents, very often oils with or without the addition of a solubilizer,a surfactant, a suspending agent or emulsifying agent are used. Examplesof oils that are used are olive oil, peanut oil, cottonseed oil, soybeanoil, castor oil and sesame oil.

[0098] The compounds of general formula II can also be formulated in theform of a solution that is intended for oral administration and that inaddition to the active compound of general formula II contains

[0099] a) a pharmaceutically compatible oil and/or

[0100] b) a pharmaceutically compatible lipophilic surfactant and/or

[0101] c) a pharmaceutically compatible hydrophilic surfactant and/or

[0102] d) a pharmaceutically compatible water-miscible solvent.

[0103] To this end, reference is made in addition to WO 97/21440.

[0104] The compounds can also be used in the form of a depot injectionor an implant preparation that can be formulated in such a way that adelayed release of the active ingredient is made possible.

[0105] Implants can contain as inert materials, for example,biodegradable polymers, or synthetic silicones such as, for example,rubber gum. In addition, the active ingredients can be added, forexample, to a patch for percutaneous administration.

[0106] For the production of intravaginal systems (e.g., vaginal rings)or intrauterine systems (e.g., pessaries, coils) that are loaded withactive compounds of general formula II, various polymers, such as, forexample, silicone polymers, ethylene vinyl acetate, polyethylene orpolypropylene, are suitable.

[0107] The compounds of general formula II according to the inventioncan be produced as described below.

[0108] The production of 11β-substituted19-nor-17α-pregna-1,3,5(10)-trien-17β-ols with a 21,16α-lactone ring canbe carried out in a one-stage process from the corresponding 17-oxocompounds or the 17α-cyanomethylated estra-1,3,5(10)-triene derivatives(non-prepublished DE 100 48 634). The formation of the iminoether andthus also the lactone is connected to the presence of a 17α-cyanomethylsubstituent.

[0109] Starting substances for the synthesis of the11β-alkyl-substituted17β-hydroxy-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactones arecompounds of general formula III

[0110] in which

[0111] R³ means a C₁₋₄-alkyl, C₂₋₆-acyl or tri(C₁₋₄-alkyl)silyl group,

[0112] R¹¹ means a straight-chain alkyl radical with 6 to 17 carbonatoms,

[0113] R¹³ means a methyl or ethyl group,

[0114] R¹⁶ means an acetyl or trimethylsilyl group.

[0115] The 11β-alkyl substitution is carried out by regioselective andstereoselective syntheses as described in the literature. Theelectrophilic estradiol derivative, for example the 5α,10α-epoxy-estr-9(11)ene derivative, is produced from anestra-5(10),9(11)-dien-17β-ol that is protected in 3-position (Teutschet al. U.S. Pat. No. 4,447,424; Faraj et al. J. Chem. Soc., Perkin Trans1, 1990, 3045-3048). Reaction with Grignard reagents R¹¹MgX (X=halogen,such as bromine, chlorine) in the presence of catalytic amounts ofcopper(I)-chloride results in the 11β-alkyl-substituted5α-hydroxy-9(10)ene derivative (Belanger et al., Steroids 37, 1981,361-382). Carried out simultaneously with the addition of acids are thedeketalization and dehydration of the 11β-alkyl-substituted compoundthat is used in a subsequent isomerization reaction with hydrogen withthe addition of a catalyst. The thus obtained 11β-alkyl-substitutedestra-1,3,5(10)-trien-17-one derivative is protected in 3-position andthen converted in the usual way to a 16α-bromine compound. Compounds ofgeneral formula II are obtained by alkaline hydrolysis and protection ofthe 16α-hydroxy function that is obtained.

[0116] As an alternative to this, the introduction of the 16-hydroxyfunction can be performed by reaction of 17-silyl- or 17-acylenol etherswith peracids and subsequent hydrolysis.

[0117] By reaction of the compounds of general formula III with lithiumacetonitrile that is produced in situ, a 17α-cyanomethyl-16α-hydroxylateis produced at an intermediate stage. By the addition of the16α-alcoholate to the nitrile group and subsequent hydrolysis of theiminoether that is formed, the lactone is formed.

[0118] By the use of compounds according to general formula III, inwhich R¹⁶ means trimethylsilyl or acetyl, a portion of about 60% of17α-cyanomethylated product can be reacted in situ in a one-pot processto form 21,16α-lactone.

[0119] The saponification of ester groupings as well as etherificationand/or esterification of free hydroxyl groups is carried out in eachcase according to established processes of organic chemistry.

[0120] The sulfamates according to the invention are accessible in a waythat is known in the art from the corresponding hydroxy steroids byesterification with sulfamoyl chlorides in the presence of a base (Z.Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)).

[0121] Subsequent acylation of the sulfamide group results in the(N-acyl)sulfamates according to the invention (cf. DE 195 40 233 A1).

[0122] The acid addition salts of the compounds of general formula IIcan also be produced according to standard processes from the free acidsof the compounds of general formula II.

[0123] The following examples are used for a more detailed explanationof the invention, without being limited thereto:

[0124] General Production Process

[0125] 8 ml (20 mmol) of n-butyllithium solution (2.5 M in toluene) iscooled to −25° C. to −35° C. while being stirred in a reaction vesselthat was rendered inert. Then, the solution is diluted by adding 8 ml oftetrahydrofuran while being cooled and reacted with 1.15 ml (22 mmol) ofacetonitrile in the above-mentioned temperature range. A white toyellowish suspension of lithium acetonitrile is produced.

[0126] A solution of 2.5 mmol of the steroid of general formula III(e.g., 1.14 g of11β-hexyl-17-oxo-estra-1,3,5(10)-triene-3,16α-diyl-diacetate) in 8 ml oftetrahydrofuran is added to this suspension while the reactiontemperature is kept from −25° C. to −35° C.

[0127] After one hour of reaction time in the above-mentionedtemperature range, the batch is mixed with water, neutralized withdilute hydrochloric acid, the tetrahydrofuran is distilled off, and thecrude product mixture is isolated by extraction with ethyl acetate.

[0128] By chromatography on silica gel 60 with an eluant mixture ofchloroform/n-hexane/methanol (45/45/10), the product can be separatedand isolated.

EXAMPLE 1

[0129]546 mg (53% of theory) of3,17β-dihydroxy-11β-hexyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactoneis obtained from 2.5 mmol (1.14 g) of11β-hexyl-17-oxo-estra-1,3,5(10)-triene-3,16α-diyl-diacetate.

[0130] In addition, the following compounds are obtained analogously:

[0131]3,17β-Dihydroxy-11β-octyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0132]3,17β-Dihydroxy-11β-decyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0133]3,17β-Dihydroxy-11β-dodecyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone

[0134] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The preceding preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0135] In the foregoing and in the examples, all temperatures are setforth uncorrected in degrees Celsius and, all parts and percentages areby weight, unless otherwise indicated.

[0136] The entire disclosure[s] of all applications, patents andpublications, cited herein and of corresponding German PatentApplication No. 102 14180.0, filed Mar. 27, 2002, and U.S. ProvisionalApplication Serial No. 60/374,516, filed Apr. 23, 2002 are incorporatedby reference herein.

[0137] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0138] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. 19-Nor-17α-pregna-1,3,5(10)-trienes with a 21,16α-lactone ring ofgeneral formula (II)

in which R³ means a hydrogen atom, a C₁₋₄-alkyl, C₂₋₆-acyl ortri(C₁₋₄-alkyl)silyl group or a group R¹⁸SO₂—, whereby R¹⁸ means a groupR¹⁹R²⁰N—, in which R¹⁹ and R²⁰, independently of one another, are ahydrogen atom, a C₁₋₅-alkyl radical, a group C(O)R²¹ and in which R²¹means a straight-chain or branched hydrocarbon radical with up to 6carbon atoms, a C₃₋₇-cycloalkyl radical, an aryl radical, an aralkylradical or an alkylaryl radical, and R¹¹ means a straight-chain alkylradical with 6 to 17 carbon atoms, and R¹³ means a methyl or ethylgroup.
 2. 11β-Substituted 19-nor-17α-pregna-1,3,5(10)-trienes with a21,16α-lactone ring according to claim 1, characterized in that thecompounds represent selective estrogen receptor α-antagonists. 3.11β-Substituted 19-nor-17α-pregna-1,3,5(10)-trienes with a21,16α-lactone ring according to claim 1, in which R¹¹ is selected fromthe group of the following side chains: hexyl, octyl, decyl, anddodecyl.
 4. 11β-Substituted 19-nor-17α-pregna-1,3,5(10)-trienes with a21,16α-lactone ring according to claim 1, in which R³ is a hydrogenatom.
 5. 11β-Long-chain-substituted 19-nor-17α-pregna-1,3,5(10)-trieneswith a 21,16α-lactone ring according to claim 1, namely3,17β-Dihydroxy-11β-hexyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone3,17β-dihydroxy-11β-octyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone3,17β-dihydroxy-11β-decyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone3,17β-dihydroxy-11β-dodecyl-19-nor-17α-pregna-1,3,5(10)-triene-21,16α-lactone6. Pharmaceutical preparations that contain at least one compound ofgeneral formula II according to claim 1 as well as a pharmaceuticallycompatible vehicle.
 7. Use of the compounds of general formula IIaccording to claim 1 for the production of pharmaceutical agents.
 8. Useof the compounds of general formula II according to claim 7 for theproduction of pharmaceutical compositions or pharmaceutical agents fortreating estrogen-dependent diseases.
 9. Use of the compounds of generalformula II according to claim 7 for the production of pharmaceuticalcompositions or pharmaceutical agents for treating breast cancers,endometrial carcinomas and prostate cancers.